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Danielle ShaferSeptember 29, 2015
Acute Leukemia
Case #1
50 year old lady is diagnosed with AML. WBC 88K with 78% blasts and platelets of 3K. She reports profound fatigue. She received a unit of PRBCs for hemoglobin of 7 and developed dyspnea. Oxygen saturation is 80% with temperature to 38.2◦C. Electrolytes are OK.
Questions
Is the diagnosis leukostasis?What is the preferred treatment?How can blood transfusion be safely given?What is the optimal treatment for
asymptomatic patients with newly diagnosed or relapsed AML and a WBC of 100K?
Hyperleukocytosis (HL)
Present in ~5 to 20% of untreated AML patients
Commonly defined as WBC>100K but can occur below arbitrary threshold Association with monocytic AML subtypes Chromosomal MLL rearrangements FLT3-ITD mutations
Primary clinical manifestations: Leukostasis DIC TLS
HL
Pathogenesis Rapid blast proliferation Disruption in normal hematopoietic cell adhesion with
reduced affinity to bone marrow
Does HL matter?
Mortality up to 8% in first 24 hours and ~20% during first week
HL is negative prognostic factor with shorter OS – even when early deaths are excluded.
DIC
Decrease in platelets and fibrinogenElevation in D-dimersProlongation of PT and aPTT
Occurs in 30 to 40% of HL-AML
Treat with FFP/fibrinogenLook for APLInitiate treatment
TLS
Up to 10% of HL-AMLProphylaxis with IVF and allopurinolClose monitoring during first days of
treatmentRasburicase for marked hyperuricemia as
lowers uric acid level by enzymatic degradation
Leukostasis
Empirically diagnosed in patients with acute leukemia, HL and respiratory or neurologic symptoms.
~44 to 50% of AML patients with WBC>100K have high probability of leukostasis
Organs affected: lung, brain, kidneyTreatment: immediate cytoreduction
Symptoms of leukostasis
Organ Symptoms
Lung Dyspnea, hypoxemia, diffuse alveolar hemorrhage, respiratory failure
Central nervous system Confusion, somnolence, dizziness, headache, delirium, coma, focal neurologic deficits
Eye Impaired vision, retinal hemorrhage
Ear Tinnitus
Heart Myocardial ischemia/infarction
Vascular system Limb ischemia, renal vein thrombosis, priapism
Hydroxyurea
Effective as short term bridging strategyDoses up to 50 to 60 mg/kg per dayNo evidence it will reduce risk of tumor lysis
Leukapheresis
Rapidly removing excessive leukocytes by mechanical separation
Able to lower WBC count by 10 to 70% in single leukapheresis
Does not replace initiation of treatment Majority of disease burden is in marrow so rapidly
mobilized after leukapheresis No consistent clinical benefit has been demonstrated
Contraindications to Leukaphersis
Cardiovascular comorbiditiesHemodynamic instabilityCoagulation disturbancesAPL
Transfusion
Judicious as it can increase blood viscosity and aggravate leukostasis
If necessary, should be administered slowly during or immediately after leukapheresis
Case #2
23 year-old-man without significant history is diagnosed with pre-B ALL. WBC is 160K with 90% blasts and 450 neutrophils. Hemoglobin is 7.5 and platelets are 10K. His electrolytes and renal function are normal. Uric acid is 11; LDH is 1500.
Case #2 questions
What is the risk of TLS?What is the optimal treatment for preventing
TLS?What is the role of rasburicase and urine
alkalinization?
TLS
Primary TLS can occur before starting treatment in malignancies with high cell turnover
Secondary TLS, more common, can occur a short time after start of treatment
TLS Risk factors
Tumor burdenPotential for rapid cell lysisPreexisting nephropathy
Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus
British Journal of HaematologyVolume 149, Issue 4, pages 578-586, 16 MAR 2010 DOI: 10.1111/j.1365-2141.2010.08143.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08143.x/full#f2
Cairo Bishop TLS (Lab)
Cairo Bishop TLS (Clinical)
TLS
Current patient at risk for TLSAggressive hydration (4000 to 5000 mL of
IVF started 24 to 48 hours before induction) to maintain urine output of 80 t0 100 ml/m2 per hour
Fix electrocytes Hyperkalemia Hyperphosphatemia Calcium if symptomatic
No evidence for urinary alkalinization
Tumour lysis syndrome: new therapeutic strategies and classification
British Journal of HaematologyVolume 127, Issue 1, pages 3-11, 22 JUL 2004 DOI: 10.1111/j.1365-2141.2004.05094.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05094.x/full#f1
TLS Drugs
Allopurinol Reduces uric acid in 1 to 3 days
Rasburicase Promotes catabolism of uric acid to allantoin Single dose likely sufficient
Case #3
59 year-old lady presents with new onset diplopia. She has third nerve palsy and CT demonstrates left occipital and thalamic infarct. CBC shows hemoglobin of 10.5, WBC of 500 and platelets of 88K. Prothrombin time is slightly prolonged with INR of 1.3 and PTT is normal. Fibrinogen is 80. BM and molecular and cytogenetics establish diagnosis of APL.
Copyright © 2011 American Society of Hematology. Copyright restrictions may apply.
Marco Gambassi, ASH Image Bank 2011; 2011-5912
Promyelocytes with Auer rods - 01
Copyright © 2011 American Society of Hematology. Copyright restrictions may apply.
Peter Maslak, ASH Image Bank 2011; 2011-4233
APL - 2.
Case Continued
What is the best prophylaxis and emergent management of coagulopathy in APL?
Coagulopathy in leukemia
In thrombohemorrhagic syndrome: Symptomatic thrombus in ~5% Symptomatic hemorrhage in ~7%
Coagulopathy in APL DIC Primary and secondary fibrinolysis and
fibrinogenolysis Incidence of fatal hemorrhage in APL is 5%
Risks include high WBC, coagulopathy, age, PS and increased creatinine.
APL early death rates
Ravindra B. Kolhe et al. Blood 2013;122:5597
©2013 by American Society of Hematology
Treatment
Early recognitionInitiation of ATRAPlatelet goal of 50K for first few daysCryoprecipitate to maintain fibrinogen > 150
Case #5
A 35-year-old man with AML is treated with induction therapy. On day 16, he develops fevers, bloody diarrhea, and right lower abdominal pain followed a few hours later by an acute abdomen. He undergoes emergency explorative laparotomy and right hemicolectomy with temporary colostomy.
Case #5 Questions
Can neutropenic enterocolitis be prevented?Should this influence the decision regarding
further chemotherapy?
Neutropenic enterocolitis (NE)
AKA necrotizing colitis, ileocecal syndrome or typhlitis
Ill defined syndrome characterized by fever and abdominal pain in setting of neutropenia Bacteremia common
Reported incidence ~6.5%
Neutropenic enterocolitis (NE)
Pathogenesis linked to damaged GI mucosa from chemotherapy and neutropenia
CT findings with thickening of bowel wall and intramural edema +/- paracolonic fluid, free air or pneumatosis intestinalis Greater than 10-mm wall thickening linked to 60%
mortality
Treatment includes bowel rest, fluid resuscitation, NG suction, parenteral nutrition and broad spectrum antibiotics.
NE – Unanswered questions
Parenteral alimentation and NG suctionQuinolone prophylaxisKeratinocyte growth factors
A bit about AML
Incidence
Most common type of acute leukemia in adults
Median age at diagnosis around 70 but can occur at any age
Estimated 18,860 people in US diagnosed in 2014
Age-Specific Incidence of AML
Data from NCI, SEER database: accessed 11/2/14
Etiology
Substantial proportion related to toxin exposure Alkylating agents
Usually 5-10 years after drug Frequently with dysplasia in all 3 lineages Usually preceding myelodysplastic phase with typical
cytogenetic abnormalities including loss of chromosome 5 or 7 Topoisomerase II inhibitors
Latency period 1-3 years Monocytic differentiation common Often with 11q23 abnormality Less often with antecedent myelodysplasia
Benzene and radiation Down syndrome
Relative survival by time and age for acute myeloid leukemia based on SEER data.
Klepin H D et al. JCO 2014;32:2541-2552
©2014 by American Society of Clinical Oncology
Ten-year relative survival curves obtained by model-based projections for 2006–2010 (black solid lines), period analysis for 2001–2005 (black dashed curves), and cohort analysis for
cohorts of patients diagnosed during 1991–1995 (gray solid lines).
D. Pulte et al. Ann Oncol 2009;21:335-341
© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
XIE et al, Nature Medicine 19 Oct 2014
Percentage of Patients in Cytogenetic Risk Groups by Age (SWOG)
Appelbaum F R et al. Blood May 2006
Byrd, J. C. et al. Blood 2002;100:4325-4336
Prognosis in AML-CytogeneticsPrognosis in AML-Cytogenetics
Breems D A et al. JCO 2008;26:4791-4797
Prognosis in AML-CytogeneticsPrognosis in AML-CytogeneticsMonosomal karyotype (MK)Monosomal karyotype (MK)
MK positive (MK+). MK refers to ≥ two autosomal monosomies or one autosomal monosomy with at least one structural abnormality
Treatment Outcome in Cytogenetically Treatment Outcome in Cytogenetically Normal AML-age < 60Normal AML-age < 60
4 year OS (%)
NPM +ve/FLT3 –ve 60
CEBPA +ve 62
FLT3 +ve 24
Wild type 33
Schlenk et al. N Engl J Med 2008;358:1909-18
Intensive Induction Options
Idarubicin (12mg/m2) IV d1-3 + Cytarabine (100-200mg/m2) CI d1-7
Daunorubicin (60mg/m2 or 90mg/m2) IV d1-3 + Cytarabine (100-200mg/m2) CI d1-7
Metaanalysis
10 studies have randomized patients to Dauno vs. Ida
N=4060 Age had a significant interaction with CR and OS
Bottom line, likely IA better in younger patients, not necessarily in older patients.
Wang et al, PLoS 2013 April
Intensive Induction in >60
Lowenberg et al. NEJM. September 24, 2009
High dose vs standard dose Daunorubicin
• 813 eligible patients.• Median follow up: 40 months. • 26% of the patients were > 71 years of age• Only 10% underwent HCT• No differences in:
• 30-day mortality (12% vs 11%), • Hospitalization• Rate of death during induction• SAE
Lowenberg et al. NEJM. September 24, 2009
SurvivalSurvival
CR 2yr OS MortalityStandard Dose 54 26 11High dose 64 31 12
Lowenberg et al. NEJM. September 24, 2009
Survival by Age
60-65
CR 2yr OS
SD 54 23
HD 64 38
66-70
CR 2yr OS
SD 59 29
HD 58 29
Lowenberg et al. NEJM. September 24, 2009
Other Options for AML therapy
Clinical trials – should be first choice in older patients, especially when not fit for intensive induction
Also Decitabine – but randomized studies indicate not
better for OS compared to supportive care Azacitadine Clofarabine
Less Intensive therapies: AMLStudy Combination N Med OS
CR rate
Other
AML 14UKMRC Burnett et al.Cancer 2007
LD-ARAC 103 <6mo 18%
OS 66 days if no CR;
565 days if CR
HU & BSC 99 <4mo 1%
MDAnderson et al.
Kantarjian et al.JCO 2012
Decitabine 242 7.7 mo 17.8%
Treatment Choice
LDARAC243 5.0 7.8%
French ATURetrospecti
veThepot et al.Blood 2009
Azacitadine Phase II
138 10.2 mo 14%
MD Anderson
Retrospective
Quintas-Cardama Blood 2012
Epigenetic therapy
both Dec and AZA
114 6.5 mo 28%
Dec > AZA with re to
OS8.8 v. 5.5